MEDICAL DEVICE GUIDANCE DOCUMENTmdb.gov.my/mdb/documents/ivd/GD_IVD_CSDT.pdf · MEDICAL DEVICE...

MEDICAL DEVICE GUIDANCE DOCUMENT

MEDICAL DEVICE CONTROL DIVISION

Ministry of Health, Malaysia

GD-XX GUIDANCE ON THE COMMON SUBMISSION DOSSIER TEMPLATE (CSDT) OF IVD MEDICAL

DEVICE

DRAFT

Common Submission Dossier Template (CSDT) of IVD Medical Device

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Table of Contents 1.0 Introduction............................................................................................................................................. 3

1.1 Purpose ................................................................................................................................................ 3

1.2 Scope.................................................................................................................................................... 3

1.3 Terms and Definitions ........................................................................................................................ 3

2.0 Preparation of a Product Registration Submission Based on the ASEAN CSDT ................................. 5

3.0 Executive Summary................................................................................................................................. 6

4. Elements Of The Common Submission Dossier Template ........................................................................... 9

4.1. Relevant Essential Principles and Method Used to Demonstrate Conformity .................................... 9

4.2. Device Description ................................................................................................................................. 11

4.2.1. Device description and features .................................................................................................... 11

4.2.2. Intended use ................................................................................................................................... 12

4.2.3. Instructions of use .......................................................................................................................... 13

4.2.4. Limitations ....................................................................................................................................... 13

4.2.5. Warnings ......................................................................................................................................... 14

4.2.6. Precautions ..................................................................................................................................... 14

4.2.7. Materials ......................................................................................................................................... 15

4.2.8. Other Relevant Specifications ........................................................................................................ 16

4.2.9. Other Descriptive Information....................................................................................................... 16

4.3. Product Verification and Validation...................................................................................................... 16

4.3.1. Pre-clinical Studies .......................................................................................................................... 17

4.3.2. Clinical Evidence ............................................................................................................................. 23

4.4. Device Labeling....................................................................................................................................... 29

4.5. Risk Analysis ........................................................................................................................................... 31

4.6. Manufacturer Information .................................................................................................................... 32

ANNEX 1 ............................................................................................................................................................. 35


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1.0 Introduction

This guidance document provides recommendations on the content of Common Submission

Dossier Template (CSDT) to be assembled and submitted to a Regulatory Authority or

Conformity Assessment Body. It shall enable a manufacturer to prepare a CSDT and

provide different Regulatory Authority or Conformity Assessment Body with the same body

of documentary evidence that its IVD medical device conforms to the Essential Principles.

The use of the CSDT shall reduce costs for the manufacturer and reviewer, remove barriers

to trade and facilitate timely international access to IVD medical devices.

This document is adopted from ASEAN CSDT and must be read in conjunction with the

Guidance to Medical Device Product Registration. Sections of the ASEAN CSDT for which

guidance has not been provided are taken to be self-explanatory.

1.1 Purpose

This document aims to provide guidance on the preparation of a product registration

application for In Vitro Diagnostic (IVD) medical devices using the ASEAN Common

Submission Dossier Template (CSDT). In particular, this document serves to clarify the

information to be submitted in each section of the CSDT and the format that this information

is to be submitted in.

1.2 Scope

This document applies to products that fall within the definition of an IVD medical device, as

defined in GD-01: Definition of Medical Device, including those used for the in vitro

examination of specimens derived from the human body.

1.3 Terms and Definitions Calibrator: Any substance, material or article intended by its product owner to be used in

the calibration of a measuring instrument or measuring system.

Control material: Any substance, material or article intended by its product owner to verify


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the performance of an IVD medical device.

Instrument: Any equipment or apparatus intended by the product owner to be used as IVD

Medical Device.

In Vitro Diagnostic (IVD) medical device: refer to GD-xx1: The Definition of Medical

Device

Lay person: Any individual that does not have formal training in a specific field or discipline

Manufacturer: (a) any person who is responsible for ―

(i) the design, production, fabrication, assembly, processing, packaging and

labeling of a medical device whether or not it is the person, or a subcontractor

acting on the person’s behalf, who carries out theses operations; and

(ii) assigning to the finished medical device under his own name, its intended

purpose and for ensuring the finished product meets the regulatory requirement;

or

(b) any other person who ―

(i) assembles, packages, processes, fully refurbishes, reprocess or labels one or

more ready-made medical devices; or

(ii) assigns to them their intended purpose as a medical device under his own

name;

but shall not include the following persons:

(a) any person who assembles or adapts the medical device in the market that is

intended for an individual patient; and

(b) any person who assembles, packages or adapts the medical device to which the

assembling, packaging or adaptation does not change the purpose intended for the

medical device.

Near patient testing: Any testing performed outside a laboratory environment by qualified

personnel, generally near to, or at the side of, the patient. Also known as Point-of-Care

(POC).


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Performance evaluation: A review of the performance of a medical device based upon

data already available, scientific literature and, where appropriate, laboratory, animal or

clinical investigations.

Reagent: Any chemical, biological or immunological components, solutions or preparations

intended by the product owner to be used as IVD medical devices.

Registrant: The person who applied for and obtained the registration of the IVD medical

device.

Self-testing: Testing performed by laypersons.

Specimen receptacle: a device, whether vacuum-type or not, specifically intended by their

product owners for the primary containment of specimens derived from the human body.

2.0 Preparation of a Product Registration Submission Based on the ASEAN CSDT

The registrant shall take note of the following pointers when preparing a CSDT dossier for

submission to MDCD:

• the prepared CSDT dossier must contain all sections, i.e. sections 3.0 to 4.6.1. Where

there are sections not applicable to the medical device, the reason for the non-

applicability shall be provided under the section heading;

• the CSDT dossier must be prepared in English;

• copies of labelling, certificates and reports that are referenced within the CSDT

submission shall be submitted as annexes to the CSDT;

• all reports submitted as part of the CSDT shall be signed-off by the product owner;

• where supporting documents such as reports or certificates are provided, every

document must be submitted in full, i.e. all the pages of a document must be

submitted;

• all copies of labelling, certificates, reports and other documents submitted must be

legible;

• all certificates submitted must be within its validity period.


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The level of detail of information to be provided under each CSDT section will depend on

the IVD medical device class and the evaluation route, i.e. abridged or full evaluation.

Registrants are advised to refer to the Guidance on Product Registration for details on the

data requirements for each IVD medical device class and evaluation route.

3.0 Executive Summary

Guidance: (a) If the medical device contains any novel features, e.g. nanotechnology, a description

of the novel feature is to be provided.

(b) For commercial marketing history, the list of countries where the medical device is marketed and the dates of introduction into each country is to be provided.

(c) For applications submitted via the abridged evaluation route, as part of the list of

regulatory approvals or marketing clearances obtained and status of any pending

request for market clearance, the following information is required:

(i) the registration status (i.e. submitted, not submitted, pending approval, rejected or

withdrawn) and intended use and indications of the medical device in all reference

ASEAN Common Submission Dossier Template, Document No.: N0013

3. Executive Summary An executive summary shall be provided with the common submission dossier template, which shall include the following information:

• an overview, e.g., introductory descriptive information on the medical device, the intended uses and indications for use of the medical device, any novel features and a synopsis of the content of the CSDT;

• commercial marketing history; • intended uses and indications in labelling; • list of regulatory approval or marketing clearance obtained; • status of any pending request for market clearance; and • important safety/performance related information.


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agencies. This information is to be provided in a tabular format as given below: Reference agency

Intended use Indications of use

Registration status and date

Reason for rejection or withdrawal (if applicable)

Note: The abridged evaluation route applies to medical devices that have been evaluated and

have obtained marketing clearances or approvals in at least one of the GHTF founding

members (Australia, Canada, European Union, Japan and United States of America).

The types of marketing clearances or approvals from each country/region that qualify for the abridged route are:

(ii) Copies of certificates or approval letters from each reference agency for the IVD

medical device are to be provided as an annex to the CSDT submission. For CE

marked devices, the declaration of conformity by the product owner must be

submitted, in addition to the EC certificate issued by the notified bodies.

(iii) declaration on labelling, packaging and instructions for use (IFU):

• if the labelling, packaging and IFU of the IVD medical device for sale in

Malaysia is identical to that approved by each reference agency, a

Country / Region Approval Type Australia Therapeutic Goods Administration (TGA) Licence Canada Health Canada Licence European Union (EU) Annex IV i.e. Section 4 and 6 of IVDD (for List A IVD)

Annex IV i.e. Section 4 and 6 or Annex V coupled with Annex VII (for List B and self-testing IVD) [Note: Classification for IVD medical device in Singapore is according to GHTF and is different from EU IVD Directive. IVD medical device products without EU approval as above-mentioned will be subjected to full evaluation route.]

Japan Ministry of Health, Labour and Welfare (MHLW) Licence United States of America (USA)

• FDA 510(K) clearance letter [Note: 510(K) exempted products do not qualify for abridged evaluation route.]; or • FDA PMA approval letter


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declaration that the labeling, packaging and IFU of the IVD medical device for

sale in Malaysia is identical to that approved by each reference agency is to

be provided.

• if the labelling, packaging and IFU of the IVD medical device for sale in

Malaysia is not identical to that approved by each reference agency, the

differences between Malaysia’s labelling, packaging and IFU and each

reference agency’s approved labelling, packaging and IFU is to be described.

The reason for the differences must also be provided.

(d) For important safety/performance related information, the following information is

to be provided:

(i) summary of reportable adverse events and field safety corrective actions (FSCA)

for the IVD medical device since its first introduction on the global market. This is

to be provided in a tabular format as given below. If there have not been adverse

events or FSCAs to date, an attestation that this is the case is required.

For reported adverse events:

Description of adverse event

Frequency of occurrence (number of reports / total units sold) in the period of dd/mm/yyyy to dd/mm/yyyy

For reported field safety corrective actions (FSCAs):

Date of FSCA Reason for FSCA Countries conducted

where FSCA was


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4. Elements of The Common Submission Dossier Template

4.1. Relevant Essential Principles and Method Used to Demonstrate Conformity ASEAN Common Submission Dossier Template, Document No.: N0013

4. Elements of the Common Submission Dossier Template

4.1 Relevant Essential Principles and Method Used to Demonstrate Conformity

The CSDT should identify the Essential Principles of Safety and Performance of Medical

Devices that are applicable to the device. The CSDT should identify the general method

used to demonstrate conformity to each applicable Essential Principle. The methods that

may be used include compliance with recognized or other standards, state of the art or

internal industry methods, comparisons to other similar marketed devices, etc.

The CSDT should identify the specific documents related to the method used to

demonstrate conformity to the Essential Principles.

4.1.1 Essential Principles and Evidence of Conformity

The evidence of conformity can be provided in tabular form with supporting documentation

available for review as required. A sample of the essential principles conformity checklist is

included in Appendix A.

For example, a completed Essential Principles conformity checklist can be used to

demonstrate that a recognized test standard was used as part of the method to

demonstrate conformity to one Essential Principle. As such, CSDT would then include a

declaration of conformity to the standard, or other certification permitted by the Regulatory

Authority, and a summary of the test data, if the standard does not include performance

requirements. When the manufacturer uses international or other standards to demonstrate

conformity with the Essential Principles, the CSDT should identify the full title of the

standard, identifying numbers, date of the standard, and the organization that created the


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standard. When the manufacturer uses other means, such as internal standards, the CSDT

should describe the means.

Not all the essential principles will apply to all devices and it is for the manufacturer of the

device to assess which are appropriate for his particular device product. In determining this,

account must be taken of the intended purpose of the device. Guidance:

The Essential Principles (EP) conformity checklist is to be prepared based on the list of EPs

found in the Regulations. The IVD medical device to which the EP conformity checklist is

applicable shall be identified on the checklist itself. Where applicable, the various

configurations of the IVD medical device covered by the checklist are to be identified in the

checklist. The columns in the recommended format for the checklist shall be completed as

follows:

(a) Applicable to the IVD medical device?

(i) Either a ‘Yes’ or ‘No’ answer is required. If the answer is ‘No’ this shall be briefly

explained. For example: For an IVD medical device that does not incorporate

biological substances, the answer to EP 9.2 would be ‘No – The IVD medical device

does not incorporate biological substances.’

(b) Method of conformity

(i) State the title and reference of the standard(s), industry or in-house test method(s),

comparison study(ies) or other method used to demonstrate compliance. For

standards, this shall include the date of the standard and where appropriate, the

clause(s) that demonstrates conformity with the relevant EP. Where a standard is

referred to more than once in the checklist, the reference number and date can be

repeated.

(c) Identity of specific documents

(i) This column shall contain the reference to the actual technical documentation that

demonstrates compliance to the EP, i.e. the certificates, test reports, study reports or


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other documents that resulted from the method used to demonstrate compliance, and

its location within the technical documentation.

4.2. Device Description 4.2.1. Device description and features

Guidance:

The following information shall be submitted to meet the requirements of this section:

(a) A general description of the principle of assay method or instrument principles of

operation.

(b) A description of all components of the IVD medical device, including but not limited

to:-

(i) antibodies, antigens, nucleic acid primers;

(ii) buffers, assay controls and calibrators;

(iii) substrates used to detect antigen-antibody complexes; and

(iv) reagents provided with the IVD medical device or recommended for use.

(c) A description of the specimen collection and transport materials provided with the IVD

ASEAN Common Submission Dossier Template, Document No.: N0013 4.2 Device Description 4.2.1 Device description and features

Besides a general description of the device, a more detailed description of the device

attributes is necessary to explain how the device functions, the basic scientific concepts that

form the fundamentals for the device, the component materials and accessories used in its

principles of operation as well as packaging. A complete description of each functional

component, material or ingredient of the device should be provided, with labeled pictorial

representation of the device in the form of diagrams, photographs or drawings, as

appropriate.


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medical device or recommended for use.

(d) For automated assays, a description of the appropriate instrumentation characteristics

or dedicated instrumentation.

(e) A description or complete list of various configurations of the IVD medical device to be

registered as a family or group, if applicable. For example, a family of pregnancy rapid

test can consist of device available in different configurations, such as a test strip or in

a cassette. This is to be provided using the Microsoft Excel template found in Annex 2.

(f) A description of the accessories, other IVD medical devices and other products that

are not IVD medical devices, which are intended to be used in combination with the

IVD medical device. For example, a lancet, which is a medical device and not an IVD

medical device that is provided in the package to the user to perform a test.

Note: Supporting documents, in CSDT format, must be provided for the medical device

accompanying the IVD medical device.

(g) Risk class and the applicable classification rule for the IVD medical device according

to the Regulations.

4.2.2. Intended use

Guidance:

The intended use of an IVD medical device shall include information on the following: (a) Type of analyte or measurand of the assay.


4.2.2 Intended use

This means the use for which the medical device is intended, for which it is suited according

to the data supplied by the manufacturer in the instructions as well as the functional

capability of the device.


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(b) Whether the test is quantitative or qualitative.

(c) Role of the test in the clinical use e.g. screening, diagnostic or detection, aid to

diagnostic, monitoring.

(d) Disease or condition that the test is intended for.

(e) Type of specimen to be used e.g. serum, plasma etc.

(f) The intended users (e.g. self-testing by lay person, near-patient by trained personnel

or professionals).

(g) Assay type e.g. immunoassay, chemistry, cytochemistry, image analysis,

immunohistochemistry.

(h) The specific name of the instrument required for the assay, if any.

For instruments, the intended use shall also include the modes of operation for instruments

e.g., random access, batch, stat, open tube, closed tube, automatic, manual.

4.2.3. Instructions of use ASEAN Common Submission Dossier Template, Document No.: N0013

4.2.3 Instructions of use

These are all necessary information from the manufacturer including the procedures,

methods, frequency, duration, quantity and preparation to be followed for safe use of the

medical device. Instructions needed to use the device in a safe manner should, to the

extent possible, be included on the device itself and/or on its packaging by other formats /

forms. There is no specific guidance for this section of the ASEAN CSDT.

4.2.4. Limitations ASEAN Common Submission Dossier Template, Document No.: N0013

4.2.4 Limitations

This is a general description of the disease or condition and the patient population for which

the device should not be used for the purpose of diagnosing, treating, curing or mitigating.


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Guidance:

For example, a limitation of an assay using specimens from patients who have received

preparations of mouse monoclonal antibodies for therapy when tested with assay kits which

employed mouse monoclonal antibodies. It may show either falsely elevated or depressed

values.

4.2.5. Warnings ASEAN Common Submission Dossier Template, Document No.: N0013

4.2.5 Warnings

This is the specific hazard alert information that a user needs to know before using the

device.

Guidance:

For products containing biological material, radioactive material, explosive material and any

other hazardous material, safety warnings must be included.

4.2.6. Precautions ASEAN Common Submission Dossier Template, Document No.: N0013

4.2.6 Precautions

This alerts the user to exercise special care necessary for the safe and effective use of the

device. They may include actions to be taken to avoid effects on patients/users that may not

be potentially life-threatening or result in serious injury, but about which the user should be

aware. Precautions may also alert the user to adverse effects on the device of use or

misuse and the care necessary to avoid such effects. There is no specific guidance for this section of the ASEAN CSDT.


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4.2.7. Materials There is no specific guidance for this section of the CSDT.

SEAN Common Submission Dossier Template, Document No.: N0013

4.2.7 Materials

This section must include complete details of material specifications, including raw

materials. a. All components of the IVD medical device shall be listed and chemically and

biologically characterised, including antibodies, antigens, assay controls, substrates

used to detect antigen-antibody complexes, and test reagents. Appropriate references

shall be cited.

b. If synthetic peptides are used, the peptide sequence shall be provided.

c. If components are of biological origin or recombinant, the source must be indicated

and details on production must be provided. These details would include the strain

of the virus, the cell line for cultivation of the virus, sequences of relevant nucleic acids

and amino acids, etc., used in the manufacturing process of viral lysate, purified

proteins, recombinant and synthetic proteins.

d. If applicable, process validation results to be provided to substantiate that

manufacturing procedures are in place to minimise biological risks, in particular, with

regard to viruses and other transmissible agents. This also includes inactivation of

infectious organisms in reagents and the production of reagents.

e. if applicable, information to be provided on irradiating components, nonionising or

ionising (e.g. Iodide-131 in the Radioimmunoassay kit, radio-labelled Phosphorus-32

DNA probes in Southern blots)

f. if applicable, information to be provided on the poison or controlled substance (e.g.

Buprenorphine in drug assay kit).


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4.2.8. Other Relevant Specifications ASEAN Common Submission Dossier Template, Document No.: N0013

4.2.8 Other Relevant Specifications

The functional characteristics and technical performance specifications for the device

including, as relevant, accuracy, sensitivity, specificity of measuring and diagnostic medical

devices, reliability and other factors; and other specifications including chemical, physical,

electrical, mechanical, biological, software, sterility, stability, storage and transport, and

packaging to the extent necessary to demonstrate conformity with the relevant Essential

Principles.

Guidance:

A list of the features, dimensions and performance characteristics of the IVD medical device

that would typically appear in the package insert and instruction manual, will satisfy the

requirements of this section.

4.2.9. Other Descriptive Information ASEAN Common Submission Dossier Template, Document No.: N0013

4.2.9 Other Descriptive Information

Other important descriptive characteristics not detailed above, to the extent necessary to

demonstrate conformity with the relevant Essential Principles. There is no specific guidance for this section of the CSDT.

4.3. Product Verification and Validation


4.3 Product Verification and Validation Documents

This section includes data from pre-clinical and clinical studies. The data required is to the

extent appropriate to the complexity and risk class of the device.


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Guidance:

For all aspects of verification and validation described in this section, where no testing was

undertaken for the IVD medical device, a rationale for that decision must be provided.

Evidence to support the rationale shall be provided.

The suitability of the IVD medical device for each of the intended specimen type, such as serum, plasma, whole blood etc, shall be verified and validated through both preclinical and clinical studies. If specimens containing anti-coagulants are recommended for use, study shall be included.

4.3.1. Pre-clinical Studies ASEAN Common Submission Dossier Template, Document No.: N0013

4.3.1 Pre-clinical Studies Information on preclinical studies to establish the safety and performance of the IVD

medical device for its intended use must be provided. The pre-clinical studies provided

should include information on study design, complete test or study protocols, methods of

data analysis, data summaries and study conclusions. The most common characteristics

that must be validated should include but are not limited to:

• Analytical Sensitivity

• Analytical Specificity and Interference

• Precision (Repeatability/Reproducibility)

• Linearity/Assay’s Measuring (Reportable) Range

• Traceability, & Expected Values

• Cut-off Value

• Trueness

• Stability of reagent

• Specimen stability

• Performance Characteristics for Instrument (if applicable):

• Accuracy


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• Precision/Reproducibility

• Linearity

• Carryover

• Interfering Substances

• Projected useful life

• Software Verification and Validation Studies

Guidance:

(a) Analytical Sensitivity

Data on analytical sensitivity shall include information on the following:

(i) The specimen type and preparation including matrix, analyte levels, and how levels

were established;

(ii) The number of replicates (runs, days, instruments, and operators, as appropriate)

included at each concentration tested;

(iii) The statistical method used;

(iv) The results of the analytical limits at low levels (e.g., limit of detection, functional

sensitivity);

(v) The definition/calculation used to determine assay sensitivity. For example:

Number of standard deviations above the mean value of the sample

without analyte. Include mean and standard deviation; and

Lowest concentration at which %CV and accuracy are within specified criteria

and describe the evaluations to determine they were met,

(vi) For qualitative assay, include the percent of replicates that test positive at each

concentration and evaluate the 95% interval for cut-off and limit of detection.

(b) Analytical Specificity and Interference

Data on analytical specificity shall include information on the following:

(i) A description of study design and statistical methods;

(ii) The specimen description and preparation including matrix, analyte levels present

in the sample, how these levels were established; and

(iii) A list of the potentially cross-reactive and interfering substances tested including


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those where a similar syndrome can be associated with more than one

analyte/agent/organism. Also include the concentrations at which these substances

were present in the samples (indicate highest concentration tested and/or lowest

concentration at which an effect was observed). Finally, include the number of

replicates tested for each substance.

(c) Precision (Repeatability/Reproducibility)

Data on precision shall include information on the following:

(i) Description of studies and results to evaluate estimates of total variability for each

specimen type. Include, as appropriate, repeatability (within-run) and reproducibility

such as between-day, between-run, within-day, between-sites, between-lots,

between instrument, and between operator(s), etc;

(ii) Description of specimens (samples) used to study variability including matrix,

sample type (e.g., patient samples, spiked samples, control material), and

preparation, including analyte levels and how they were established. The

relationship between the analyte levels to measuring (reportable) range and

medical decision points must also be described;

(iii) Description of sources of variability examined (e.g., runs, instruments, operators,

days; sites at which variability studies were performed; reagent lots and

instruments studies with identifying information);

(iv) Description of statistical methods used to analyse data; include any model

assumptions;

(v) For quantitative or qualitative assays with numerical values, the number of

measurements, mean, standard deviation, and %CV for each parameter tested and

for each level tested; and

(vi) For qualitative assays, the number of replicates, the concentration of the sample,

the number of positive and negative results, and the number of invalid or equivocal

results, if applicable. For reproducibility studies on qualitative tests, an estimation of

the precision of the method at analyte concentrations near the cut-off.


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(d) Linearity/Assay’s Measuring (Reportable) Range

Data on linearity/assay’s measuring shall include information on the following:

(i) The linear range, measuring (reportable) range and information on how these were

established. For quantitative and semi-quantitative assays, the analytical data to

support linearity and the description on the recovery of the assay in graphic and

tabular form;

(ii) The linear range and measuring (reportable) range. Include the measure of

deviation from linearity, if applicable;

(iii) Description of how reportable range is determined including acceptable criteria or

results for accuracy, precision, or other characteristics within this range;

(iv) Description of specimen type and preparation including information on matrix,

analyte levels, and the methods used to determine the target levels;

(v) The number of samples, the number of replicates, and the statistical methods used;

(vi) The results such as estimates of slope, intercept with confidence intervals, and R2

value of regression;

(vii) Provide the range of percent recovery at each concentration (observed value/target

value);

(viii) Description on how results outside the measuring (reportable) range are reported

to the user;

(ix) Description on the validation of instructions for out-of-range specimens, if

applicable; and

(x) Discussion of possible high-dose hook effect, if applicable.

(e) Traceability & Expected Values (Controls, Calibrators, Methods)

Data on traceability and expected values shall include information on the following:

(i) Where applicable, summary information about traceability of calibrators and

trueness control material. Include for examples, methods and acceptable criteria for

traceability to reference material and description of value assignment and

validation; and

(ii) A description on how the recommended calibration and control testing frequency


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were established, validation of the standard curve by replicate analysis of

calibrators, and validation of quality control, as appropriate (e.g., novel, internalised

quality control).

Note: Precision control material used for establishing reproducibility does not require

traceability to reference material.

(f) Cut-off Value Data on cut-off value shall include information on the following: (i) The rationale for the units, cut-off and/or categories of the results;

(ii) A description of specimen preparation including analyte levels, matrix, and how the

level was established;

(iii) The statistical method used (e.g., Receiver Operator Characteristic Analysis); and

(iv) A definition of equivocal zone, if applicable.

(g) Trueness Data on trueness shall include information on the following: (i) The measure of trueness in the closeness of agreement between the average value

obtained from a large series of test results and an accepted reference value; and

(ii) Bias of the measurement procedure shall be determined by a suitable recovery or

comparison of procedures experiments, and provides the methodology and the rational

of its use.

(h) Stability of reagent

Data on stability of reagent shall include information on the recommended shelf life or

storage conditions for in use or opened and unopened IVD medical device, and also taking

into consideration of variable conditions including temperature, freeze/thaw cycle and its

duration during usage (including for on-board use), and for transportation. The studies shall

be provided from at least 3 lots or batches. If real-time stability is not available, an

accelerated study is acceptable for initial shelf life claim while continuing real time studies to

be performed. Statistical method used also to be provided. The final real time study report


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must be submitted when completed.

(i) Specimen stability

Data on specimen stability shall include information on the following: (i) Description of the recommended method for the specimen’s collection, storage and

transportation; and

(ii) The specimen stability validation studies for the collection, storage and transportation

methods. Elements to be validated would include but not limited to storage duration,

temperature limits, and freeze/thaw cycle.

(j) Performance Characteristics for Instrument (if applicable): Data to support the performance characteristics for instruments shall include information on

the following:

(i) Accuracy

Comparison information on each test parameter to either a reference method or an

IVD medical device with the same intended use. The testing pool shall contain

samples representative of the appropriate population, including an equal number of

males and females for which samples span the reportable range. Specimens that are

close to the clinically critical decision point(s) must be included. Data to be presented

using linear regression, including 95% confidence intervals for the slope and y-

intercept and scatter plots.

(ii) Precision/Reproducibility

Estimation of intra, inter, lot-to-lot, operator-to-operator, and total imprecision for

each measurand parameter of the IVD medical device using samples that span the

testing range.

(iii) Linearity

Information on how linearity was established and indication on whether this

conformed to any available reference or methodology.


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(iv) Carryover

Studies to demonstrate lack of over estimation of results due to the carryover effect.

The testing pool shall consist of samples at clinically meaningful levels. For

investigation of potential carry-over, at least five runs with alternating high-positive

and negative specimens shall be performed during robustness studies. The high

positive samples shall comprise of samples with naturally occurring high virus titres.

(v) Interfering Substances

Studies to show possible interference of substances such as lipids, haemoglobin,

bilirubin, etc.

(vi) Projected useful life

For IVD medical device that does not have expiry dates, the projected useful life of

the IVD medical device must be provided. Product owners may refer to TS/ISO

14969 (Medical devices – Quality management systems – Guidance on the

application of ISO 13485:2003) for information on how to determine the projected

useful life.

(vii) Software Verification and Validation

The correctness of a software product is a critical product characteristic that cannot

be fully verified in a finished product. The product owner must provide evidence that

validates the software design and development process. This information shall

include the results of all verification, validation and testing performed in-house and in

a user's environment prior to final release, for all of the different hardware

configurations identified in the labelling, as well as representative data generated

from both testing environments.

4.3.2. Clinical Evidence ASEAN Common Submission Dossier Template, Document No.: N0013

4.3.2 Clinical Evidence

This section should indicate how any applicable requirements of the EPs for clinical

evaluation of the device have been met. Where applicable, this evaluation may take the


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form of a systematic review of existing bibliography, clinical experience with the same or

similar medical devices, or by clinical investigation. Clinical investigation is most likely to be

needed for higher risk class medical devices, or for medical devices where there is little or

no clinical experience.

Guidance:

The clinical evidence to be provided shall include the information mentioned in this section. For Class D IVD medical device, if discrepant test results are identified as part of an

evaluation, these results shall be resolved as far as possible, using one or more of the

following approaches:-

by evaluation of the discrepant sample in further test systems,

by use of an alternative method or marker,

by a review of the clinical status and diagnosis of the patient, and

by the testing of follow-up-samples.

(a) Clinical (Diagnostic) Sensitivity

Data on clinical (diagnostic) sensitivity shall include information on the following:

(i) The methodology including its statistical method, results, discussion and

conclusion for the study;

(ii) The total individual positive specimens and the sero-conversion panels used in

the study. For positive specimens, where different virus subtypes and genotypes

are available, studies of these subtypes specimens must be included. For Class D

IVD medical device, when testing the sero-conversion specimens, the diagnostic

sensitivity during the early infection phase (sero-conversion) has to represent the

state of the art;

(iii) The probability that the IVD medical device gives a positive result in the presence

of the target marker; and

(iv) Negative predictive values to be included in the calculation.


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(b) Clinical (Diagnostic) Specificity Data on clinical (diagnostic) specificity shall include information on the following:

(i) The methodology including its statistical method, results, discussion and

conclusion for the study;

(ii) The total individual negative specimens in the study. Negative specimens used in

a performance evaluation shall be defined so as to reflect the target population for

which the test is intended, for example blood donors, clinical samples or

hospitalised patients including pregnant women, and potentially interfering

samples;

(iii) The probability that the IVD medical device gives a negative result in the absence

of the target marker; and

(iv) Positive predictive values to be included in the calculation.

(c) Comparison Studies Using Clinical Specimens

Comparison studies using clinical specimens shall include information on the

following:

(i) Method comparison: All performance evaluations shall carry out in direct

comparison with an established state of the art IVD medical device. The

established product for comparison must have obtained marketing clearance from

the reference agencies, namely Australia TGA, Canada TPP, Europe, Japan

MHLW, and US FDA.

Study design shall include:

description on the test methods,

information on the comparator(s) (e.g., reference IVD medical

device, reference method), the sample type(s) (e.g., unaltered patient specimens, spiked or diluted

patient specimens, spiked patient pools, and control material), matrix,

number of samples, sample range,

when appropriate, number/types of sites, sample selection methods,

inclusion/exclusion criteria, overall demographic description of patients


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represented by the samples (e.g., age, gender, race, how/whether samples

represent the intended use population), number of individuals represented,

and

statistical methods used to generate results (e.g., regression methods, data

exclusion, number of observation represented by each data point).

Results shall include:

Description on the overall results and/or results from specific sites and

patient groups, as appropriate,

For quantitative tests, information such as slope and intercept (with

confidence intervals), correlation coefficient, measure of scatter around the

regression line, measure of bias at medical decision levels. In some cases,

a graph (x-y graph or bias plot) can be included, and

For qualitative or semi-quantitative tests, percent agreement with

comparator for positive/negative samples, confidence intervals.

(ii) Matrix comparison:

Study design shall include:

for each matrix in the intended use, the method for comparison or

determination of accuracy, and

sample types tested, number of samples, sample range or target

concentrations tested and calculations/statistical methods.

Results/Acceptance criteria shall include:

the accuracy of the new matrix or results of the matrix comparison.

(d) Clinical Cut-off

This information shall include: (i) The established cut-off and its validation for the new IVD medical device; and

(ii) If applicable, the “equivocal zone” is to be defined, and include a description of

how results within this zone are reportable to the user.


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(e) Reference Interval (Expected Values) This information shall include:

(i) The reference interval for this measured and the method used to determine it;

(ii) The literature references establishing the reference intervals and justification

for applying this range to the new IVD medical device;

(iii) A description of the methods for determining the reference intervals if they are

not well established from the literature or if the range cannot be transferred to

the new IVD medical device;

(iv) The description of the population studies (demographics, inclusion/exclusion

criteria, number of individuals);

(v) Any separate reference intervals for subclasses where clinically justified;

(vi) The method of clinical diagnosis of the reference population(s); and

(vii) The statistical method used to calculate the ranges.

(f) Additional requirements for IVD medical device for self-testing and near patient testing

(if applicable)

The field evaluation report shall be provided. Study results and data shall:-

(i) show the handling suitability of the IVD medical device; and

(ii) determine the IVD medical device’s performance when used by the intended

users following instructions provided in the labelling and without the assistance

from the professionals.

Also, there shall be a study to show that the correct result can be obtained by the

intended users, when compared to the laboratory professionals.


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4.3.2.1. Use of Existing Bibliography ASEAN Common Submission Dossier Template, Document No.: N0013

4.3.2.1 Use of Existing Bibliography

Copies are required of all literature studies, or existing bibliography, that the manufacturer is

using to support safety and effectiveness. These will be a subset of the bibliography of

references. General bibliographic references should be medical device-specific as supplied

in chronological order. Care should be taken to ensure that the references are timely and

relevant to the current application.

Clinical evidence of effectiveness may comprise device-related investigations conducted

domestically or other countries. It may be derived from relevant publications in a peer-

reviewed scientific literature. The documented evidence submitted should include the

objectives, methodology and results presented in context, clearly and meaningfully.

The conclusions on the outcome of the clinical studies should be preceded by a discussion

in context with the published literature.

Guidance:

Critical review analysis and evaluation of literature studies or existing bibliography are broad

concepts, which include any experience gained from an established IVD medical device

already on the market and used in clinical practice. A written report containing a critical

review analysis and evaluation of the literature studies compilation must include the

objectives, methodology, results, discussion and a conclusion to demonstrate that such

data support the intended purpose, the design, the materials, its procedures, the safety and

performance of the IVD medical device.


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4.4. Device Labeling ASEAN Common Submission Dossier Template, Document No.: N0013

4.4 Device Labeling

The device labeling refers to any written, printed or graphic representation affixed to a

medical device or any part of its packaging, or accompanying a medical device, when the

medical device is being supplied.

This section should summarize or reference or contain the following labelling data to the

extent appropriate to the complexity and risk class of the device, which is generally

considered as “labeling”: • Labels on the device and its packaging; • Instructions for use; • Physician’s manual

Any information and instructions given to the patient, including instructions for any

procedure the patient is expected to perform (if applicable).

4.4.1 Samples of Labels on the Medical device and its Packaging

This is the printed, written or graphic product information provided on or attached to one or

more levels of packaging, including the outer packaging or the outside container wrapper.

Any pack labelling, which is not provided on the outer packaging must be easily legible

through this outer packaging.

If it is physically impossible to include samples of labels (e.g. large warning labels affixed

onto an X-ray machine), alternative submission methods (e.g. photographs or technical

drawings), to the extent appropriate, will suffice to meet the requirements of this section.

4.4.2 Instructions for Use

The instructions for use is commonly referred to as the physician’s manual, user manual,

operator’s manual, prescriber’s manual or reference manual. It contains directions under


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which the physician or end-user can use a device safely and for its intended purpose. This

should include information on indications, contraindications, warnings, precautions, potential

adverse effects, alternative therapy and the conditions that should be managed during

normal use to maintain the safety and effectiveness of the medical device.

Guidance:

The submission dossier shall typically contain a complete set of labeling associated with the

IVD medical device as prescribed in the Regulation. The following information is to be

provided:

(a) The labels

(i) The labels on the IVD medical device and its packaging are to be provided for the

primary and secondary levels of packaging and shall be provided in the original

colour. The labels can be provided in the form of artwork.

(ii) Labels provided must be in English.

(iii) Labels must be provided for all the components of an IVD medical device system,

members of a IVD medical device family and accessories submitted for

registration. Alternatively, a representative label may be submitted for variants,

provided the variable fields on the artwork are annotated, and the range of values

for the variable fields are indicated.

(b) The instructions for use shall contain information on the proper use of the IVD medical

device, such as:-

(i) the intended use,

(ii) directions for use,

(iii) limitations,

(iv) warnings,

(v) precautions,

(vi) materials,

(vii) storage requirements,

(viii) expiration/stability dating,


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(ix) specimen handling and its storage requirements,

(x) results (calculations, formulas, interpretation),

(xi) performance characteristics (summarise analytical and diagnostic sensitivity,

specificity, reproducibility, etc.), and

(xii) study design (population studies, N, type of sample, matrix, dilution, target

concentrations, etc.).

(c) Apart from IVD medical device labeling, the promotional material and product

brochures shall be provided in this section to aid in the evaluation of the IVD medical

device.

Note: Inclusion of promotional materials as part of the submission requirement for CSDT does not constitute approval by the Authority of the claims contained within the promotional materials.

4.5. Risk Analysis ASEAN Common Submission Dossier Template, Document No.: N0013

4.5 Risk Analysis

This section should summarize or reference or contain the results of the risk analysis. This

risk analysis should be based upon international or other recognized standards, and be

appropriate to the complexity and risk class of the device.

4.5.1 Results of Risk Analysis

A list of possible hazards for these devices must be prepared. Indirect risks from medical

devices may result from device-associated hazards, such as moving parts, which lead to

sustained injury, or from user-related hazards, such as ionizing radiation from an X-ray

machine. The evaluation of these risks against the claimed benefits of the device and the

method(s) used to reduce risk to acceptable levels must be described. The individual or

organization that carries out the risk analysis must be clearly identified. The technique used

to analyze risk must be specified, to ensure that it is appropriate for the medical device and

the risk involved.


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Guidance: Information required in this section is to be provided in the form of a risk management

report. It is recommended that the risk management activities be conducted according to

ISO 14971. A risk management report will contain details of the risk analysis, risk

evaluation, risk control conducted for the IVD medical device. The risks and benefits

associated with the use of the IVD medical device shall be described.

4.6. Manufacturer Information ASEAN Common Submission Dossier Template, Document No.: N0013

4.6 Manufacturer Information

This section should summarize or reference or contain documentation related to the

manufacturing processes, including quality assurance measures, which is appropriate to the

complexity and risk class of the medical device.

4.6.1 Manufacturing Process

Manufacturing process for the medical device should be provided in the form of a list of

resources and activities that transform inputs into the desired output.

EXAMPLE: The manufacturing process should include the appropriate manufacturing

methods and procedures, manufacturing environment or condition, and the facilities and

controls used for the manufacturing, processing, packaging, labelling, storage of the

medical device. Sufficient detail must be provided to enable a person generally familiar with

quality systems to judge the appropriateness of the controls in place. A brief summary of the

sterilization method and processing should be included, if any.

If multiple facilities are involved in the manufacture of medical device, the applicable

information (e.g. quality assurance certificates issued by an accredited third party inspection

body) for each facility must be submitted. Firms that manufacture or process the medical

device under contract to the manufacturer may elect to submit all or a portion of the


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manufacturing information applicable to their facility directly to the Regulatory Authority in

the form of a master file. The manufacturer should inform these contractors of the need to

supply detailed information on the medical device. However, it is not the intent of this

section to capture information relating to the supply of sub-components (i.e. unfinished

medical device) that contributes towards the manufacture of the finished medical device

itself.

Guidance: (a) Information on the manufacturing process shall be provided in sufficient detail to

allow a general understanding of the manufacturing processes. Detailed proprietary

information on the manufacturing process is not required. The information may be

presented in the form of a process flow chart showing an overview of production,

controls, assembly, in-process and final product testing, and packaging of the finished

IVD medical device.

(b) If the manufacturing process is carried out at multiple sites, the manufacturing

activities carried out at each site shall be clearly identified. For example:

(i) If the manufacturing process of a product consists of a number of subassembly

processes, the manufacturing sites where each of these subassembly processes

are carried out must be identified, and the relationship between these processes

must be shown; or

(ii) If multiple sites manufacture the same product, each of these sites must be

identified. The sites (including contract manufacturers) where design and

manufacturing activities are performed shall be identified.

(c) Quality Management System certificates are to be provided for the design and

manufacturing sites (including contract manufacturers) as an annex to the CSDT

submission. This requirement does not apply to raw material manufacturers (for

example, contract manufacturers of sodium azide).

(d) For Class D IVD medical device, the batch release plan shall be provided to


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demonstrate that each batch consistently identifies the relevant antigens, epitopes,

and antibodies. The batch release plan shall be provided as an annex, with detailed

information on the establishment of the batch release panel, including the number of

positive and negative panel.


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ANNEX 1 Example of an Essential Principles Conformity Checklist

Essential Principle Applicable to the device?

Method of Conformity

Identity of Specific Documents

1. Medical devices should be designed and manufactured in such a way that, when used under the conditions and for the purposes intended and, where applicable, by virtue of the technical knowledge, experience, education or training of intended users, they will not compromise the clinical condition or the safety of patients, or the safety and health of users or, where applicable, other persons, provided that any risks which may be associated with their use constitute acceptable risks when weighed against the benefits to the patient and are compatible with a high level of protection of health and safety.

2. The solutions adopted by the product owner for the design and manufacture of the devices shall conform to safety principles, taking account of the generally acknowledged state of the art. When risk reduction is required, the product owner shall control the risk(s) so that the residual risk(s) associated with each hazard is judged acceptable. The product owner shall apply the following principles in the priority order listed: • identify known or foreseeable hazards and estimate the associated risks arising from the intended use and foreseeable misuse, • elimate risks as far as reasonably practicable through inherently safe design and manufacture, • reduce as far as is reasonably practicable the remaining risks by taking adequate protection measures, including alarms, • inform users of any residual risks.

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